Emily C. Walvoord

The Timing of Puberty: Is It Changing? Does It Matter?

Whether the secular trend of a decreasing age of puberty has continued over the past 50 years remains controversial. Data that had been classically used to address this issue are reviewed and large epidemiologic studies, which had not previously been included, are now considered to challenge the conclusions of prior debates of this topic. The effect and timing of excessive weight gain are discussed in detail and recent observations about the opposing effects of obesity on the pubertal timing of girls versus boys are considered. The second half of the review examines both the causes and the long-term health consequences of early puberty, touching on the possible effect of stress and endocrine-disrupting chemicals along with the risks of reproductive cancers, metabolic syndrome, and psychosocial consequences during adolescence and beyond.

Roles of the LHX3 and LHX4 LIM-Homeodomain Factors in Pituitary Development

The LHX3 and LHX4 LIM-homeodomain transcription factors play essential roles in pituitary gland and nervous system development. Mutations in the genes encoding these regulatory proteins are associated with combined hormone deficiency diseases in humans and animal models. Patients with these diseases have complex syndromes involving short stature, and reproductive and metabolic disorders. Analyses of the features of these diseases and the biochemical properties of the LHX3 and LHX4 proteins will facilitate a better understanding of the molecular pathways that regulate the development of the specialized hormone-secreting cells of the mammalian anterior pituitary gland.

Inhaled Growth Hormone (GH) Compared with Subcutaneous GH in Children with GH Deficiency: Pharmacokinetics, Pharmacodynamics, and Safety

BACKGROUND Delivery of GH via inhalation is a potential alternative to injection. Previous studies of inhaled GH in adults have demonstrated safety and tolerability. OBJECTIVE We sought to assess safety and tolerability of inhaled GH in children and to estimate relative bioavailability and biopotency between inhaled GH and sc GH. DESIGN/METHODS This pediatric multicenter, randomized, double-blind, placebo-controlled, crossover trial had two 7-d treatment phases. Patients received inhaled GH and sc GH in the alternate phase. Placebo was administered by the route opposite from active drug. GH and IGF-I levels were measured at multiple time points. Pharmacokinetics were assessed using noncompartmental methods. RESULTS Twenty-two GH-deficient children aged 6-16 yr were treated. Absorption of GH appeared to be faster after inhalation with maximum serum concentrations measured at 1-4 h compared with 2-8 h for sc GH. Mean relative bioavailability for inhaled GH was 3.5% (90% confidence interval 2.7-4.4%). Mean relative biopotency, based on IGF-I response, was 5.5% (confidence interval 5.2-5.8%). Similar dose-dependent increases in mean serum GH area under the curve and IGF-I changes from baseline were seen after inhaled and sc GH doses. Inhaled GH was well tolerated and preferred to injection. No significant changes in pulmonary function tests were seen. CONCLUSIONS In this first pediatric trial of GH delivered by inhalation, it was well tolerated and resulted in dose-dependent increases in serum GH and IGF-I levels. This study establishes that delivery of GH via the deep lung is feasible in children.

The role of homeodomain transcription factors in heritable pituitary disease.

The anterior pituitary gland secretes hormones that regulate developmental and physiological processes, including growth, the stress response, metabolic status, reproduction and lactation. During embryogenesis, cellular determination and differentiation events establish specialized hormone-secreting cell types within the anterior pituitary gland. These developmental decisions are mediated in part by the actions of a cascade of transcription factors, many of which belong to the homeodomain class of DNA-binding proteins. The discovery of some of these regulatory proteins has facilitated genetic analyses of patients with hormone deficiencies. The findings of these studies reveal that congenital defects—ranging from isolated hormone deficiencies to combined pituitary hormone deficiency syndromes—are sometimes associated with mutations in the genes encoding pituitary-acting developmental transcription factors. The phenotypes of affected individuals and animal models have together provided useful insights into the biology of these transcription factors and have suggested new hypotheses for testing in the basic science laboratory. Here, we summarize the gene regulatory pathways that control anterior pituitary development, with emphasis on the role of the homeodomain transcription factors in normal pituitary organogenesis and heritable pituitary disease.

Normal and Abnormal Growth

Growth has been described as the work of childhood. Very few things are as important, or as good a barometer of a child’s health, as his or her growth. Under normal circumstances, growth proceeds in a predictable fashion from conception to adulthood. Abnormal growth can be a harbinger of a pathologic condition of any organ system, as well as a psychosocial problem.

Low hemoglobin levels in children with in idiopathic growth hormone deficiency.

Multiple lines of evidence have implicated the growth hormone (GH) axis in the regulation of erythropoiesis. To test the hypothesis that GH deficiency is associated with hematologic abnormalities, we analyzed pretreatment hemoglobin levels in 100 children with GH deficiency. Hemoglobin levels were decreased in children with GH deficiency compared with age-corrected norms.

A competency-based approach to recruiting, developing, and giving feedback to department chairs.

Academic health centers (AHCs) are under unprecedented pressure, making strong leadership during these challenging times critical. Department chairs have tremendous influence in their AHCs, yet data indicate that--despite outstanding academic credentials--they are often underprepared to take on these important leadership roles. The authors sought to improve the approach to recruiting, developing, and giving feedback to department chairs at their institution, the Indiana University School of Medicine (IUSM), by reorganizing these processes around six key leadership competencies: leadership and team development, performance and talent management, vision and strategic planning, emotional intelligence, communication skills, and commitment to the tripartite mission. Over a two-year period (2009-2011), IUSM faculty and administrators developed standardized recruitment procedures to assess potential chairs based on the six leadership domains, and searches are now streamlined through centralized staff support in the deans office. Additionally, IUSM offers a chair development series to support learning around these leadership competencies and to meet the stated professional development needs of the chairs. Finally, chairs receive structured feedback regarding their leadership (among other considerations) through two different assessment instruments, IUSMs Department Chair 360° Leadership Survey and IUSMs Faculty Vitality Survey--both of which the dean reviews annually. Strategically attending to the way that chairs are selected, developed, and given feedback has tremendous potential to increase the success of chairs and, in turn, to constructively shape the culture of AHCs.

Seminoma and a gonadoblastoma in an infant with mixed gonadal dysgenesis

The genital examination of a newborn with ambiguous genitaliarevealedanenlargedphallicstructure,asingleanterior perineal opening, and fused labioscrotal folds with no palpable gonads (Fig 1). No Turner syndrome stigmata were present. The testosterone level was 29 ng/dL (normal range for female newborns, 20-64 ng/dL; males, 75-400 ng/dL), and a mullerian inhibitory substance was undetectable. Chromosome analysis revealed a 45,X/46,XY mosaic karyotype. A normal uterus and kidneys were identified by ultrasonogram, and a urogenital sinus was present on cystourethrogram. The family selected a female gender for the baby. At9monthsofage,theinfanthadbilateralgonadectomy and feminizing genital surgery. Intraoperative findings confirmed a low confluence urogenital sinus with a well-formed vagina. A streak gonad with a normal fallopian tube and hemiuterus were present on the right. The left gonad was torsed and free-floating in the abdomen without identifiable ductal structures. Pathologic examination of the right gonad showed a testis-streak with seminiferous tubules containing placental alkaline phosphatase-positive (PLAP) cells, consistent with intratubular germ cell neoplasia, and peripheral streak gonadal tissue with multifocal areas of gonadoblastoma (Fig 2, B). The left gonad consisted of an encapsulated 2.0 3 1.8 3 0.6 cm soft tissue mass with diffuse coagulative necrosis and dystrophic calcifications consistent with torsion. Sheets of monomorphic large round cells surrounded by fibrous septae (Fig 2, A) were identified, consistent with a seminoma. A computed tomography scan of the abdomen, pelvis, and chest showed no evidence of metastasis. Beta-human chorionic gonadatropin and a-fetoprotein levels were normal. We describe a unique case of bilateral gonadal tumors occurring in an infant with mixed gonadal dysgenesis (MGD). MGD is an intersex disorder characterized by asymmetric dysgenetic gonads, ambiguous genitalia, persistent mullerian structures, and a Y cell line. Patients with MGD are at high risk of developing gonadal tumors, the majority being identified in the second and third decade of life. The most common tumor is a gonadoblastoma, a benign lesion composed of dysplastic germ and sex cord cells. However, the germ cell element can give rise to malignant germinomas such as seminomas, as in our case. 1,2 Prophylactic gonadectomy is indicated, but there are no clear recommendations as to when this should occur. The young age of this child emphasizes the importance of very early gonadectomy in patients with MGD that are to be raised in the female gender, and careful monitoring of male infants after early orchiopexy.

Peptides derived from pro-growth hormone-releasing hormone activate p38 mitogen-activated protein kinase in GH3 pituitary cells

Posttranslational processing of the pro-growth hormone-releasing hormone (proGHRH) peptide can result in the formation of at least two peptide products: GHRH and the C-terminal peptide, GHRH-related peptide (GHRH-Rp). While cyclic adenosine monophosphate transduces many of the actions of GHRH, other pathways also have been implicated in its actions. The aims of this study were to examine and characterize the activation of mitogen-activated protein kinase (MAPK) pathways by GHRH, and GHRH-RP in pituitary-derived GH3 cells, as well as the activation of the transcription factors that serve as substrates for these kinases. GHRH rapidly increased p44/p42 MAPK activity in GH3 cells in a protein kinase A-dependent and a protein kinase C-independent manner and stimulated the activation of the transcription factor Elk-1. By contrast, GHRH-RP, and p75-92NH2 had no effect on p44/p42 MAPK phosphorylation in these cells. Additionally, we determined that all three peptides, GHRH, GHRH-RP, and p75-92NH2, rapidly and specifically increase phosphorylation of p38 MAPK and stimulate the activation of the nuclear factor CHOP. These are the first studies to demonstrate the activation of Elk-1 by GHRH and the activation of p38 MAPK and CHOP by GHRH, GHRH-RP, and p75-92NH2. We conclude, that members of the GHRH family of peptides differentially activate multiple intracellular signaling pathways and suggest that the biologic actions of GHRH may be far more diverse than previously thought.

Extreme Hyperglycemia and Hyperosmolar State in New Onset Type 1 Diabetes: Are Sugar- and Salt-Containing Beverages at Fault?

The hyperglycemic hyperosmolar state (HHS) is an acute complication of diabetes mellitus generally thought to occur in individuals with type 2 diabetes mellitus (T2DM) and usually in older patients who are dependent on others for support.1 Although HHS is infrequently encountered in children, it is associated with a mortality rate of approximately 15%.2 Some reports have implicated high-carbohydrate-containing beverages in causing exaggerated hyperglycemia and hyperosmolarity, resembling the clinical and laboratory picture of HHS, in the acute presentation of type 1 diabetes mellitus (T1DM).3,4 With the high case fatality rates associated with HHS, patients with diabetes presenting in a similar manner require prompt identification to ensure adequate fluid replacement and gradual correction of serum osmolarity.5 The following cases describe 3 children seen at our institution with new onset T1DM and severe hyperglycemia, hypernatremia, and hyperosmolarity. Although these cases are not classic for HHS due to the presence of ketones,5 the clinical presentation and other biochemical abnormalities are comparable. Each child required a prolonged hospital stay and intensive fluid management to correct fluid and electrolyte abnormalities. The clinical and biochemical characteristics of all 3 cases are described in Table 1. The potential influence of high-carbohydrate- and high-sodium-containing beverages is discussed. Table 1 Clinical and Biochemical Characteristics of 3 Boys at Presentation With New Onset Type 1 Diabetes Mellitus Case Reports Case 1 A 9.6-year-old prepubertal white male presented with a week history of flu-like symptoms. Parents noted polydipsia, polyuria, and vomiting 2 days prior to admission. He drank 4 liters of soft drinks in a 14-hour period, resulting in consumption of approximately 217 g of carbohydrates and 392 mg of sodium. He was noted to have hyperglycemia, hypernatremia, hyperosomolarity, and acidosis (Table 1). He initially received 1 liter of normal saline and was then started on 5% dextrose in half normal saline at maintenance. He was also placed on an insulin drip at 0.1 U/kg/h and transported to our medical center. At our hospital, his serum glucose was 756 mg/dL and serum sodium was 159 mEq/L. He had acute neurologic changes, including decreased activity, impaired cognition, and incoherent speech. One dose of mannitol was administered, and a head computed tomography showed no intracranial abnormalities or cerebral edema. After 16 hours of IV fluids (IVF), he was switched to 5% dextrose in quarter normal saline at 1.5 times maintenance to correct his hypernatremia. After his neurologic status returned to baseline, he was transferred to the pediatric floor. Serum sodium was 156 mEq/L, serum glucose was 163 mg/dL, and acidosis had resolved. He was started on subcutaneous insulin and allowed to eat but was maintained on IVF for another 24 hours. IVF were discontinued on the fourth day of admission when his serum sodium was 137 mEq/L. In total, he received 6100 mL (175 mL/kg) of IVF. At his follow-up clinic visit, he did not demonstrate any neurologic sequelae.